Lecture 28 Cholesterol PDF

Final examination: Tuesday 10th Dec. 8:30 -10:30 (THRN 1307) Friday 6th December, Course review Synthesis of storage lipids Triglycerides Cholesterol  Synthesis of Triacyl Glycerols (TAGs) Begins by synthesizing phosphatidic acid (PA) from G3P PA = precursor to TAGs and phospholipi...

Final examination: Tuesday 10th Dec. 8:30 -10:30 (THRN 1307) Friday 6th December, Course review Synthesis of storage lipids Triglycerides Cholesterol  Synthesis of Triacyl Glycerols (TAGs) Begins by synthesizing phosphatidic acid (PA) from G3P PA = precursor to TAGs and phospholipids. – Fatty acids converted to acyl- CoA (synthetase) – attached to glycerol backbone by acyl transferases – releases CoA Phosphatidic Acid - forms TAGS or Phospholipids Phosphatidic acid phosphatase (lipin) removes the 3-phosphate from the phosphatidic acid. – yields 1,2-diacylglycerol The third carbon can be acylated with a third fatty acid. – yields triacylglycerol Or - attachment of polar head group – membrane lipids  Cholesterol, Steroids, and Isoprenes Chemically related Distinct from TAGs, phospholipids, sphingolipids Built on biosynthesis using 5-carbon isoprene unit Overview of Eukaryotic Cholesterol Biosynthesis 1. Three acetates condense to form mevalonate. 2. Mevalonate converted to phosphorylated 5-C isoprene. 3. Six isoprenes polymerize to form the 30-C linear squalene. 4. Squalene cyclizes to form the four rings that are modified to produce cholesterol. Formation of Mevalonate from Acetyl-CoA Three acetyl-CoA are condensed to form hydroxymethylglutaryl- CoA (HMG-CoA). HMG-CoA is reduced to form mevalonate. HMG-CoA reductase is a common target of cholesterol-lowering drugs. Steroid Hormones Derived from Cholesterol  Statin Drugs Inhibit HMG-CoA Reductase - Lower Cholesterol Synthesis Statins resemble mevalonate → competitive inhibitors of HMG-CoA reductase First statin, lovastatin, found in fungi – lowers serum cholesterol by tens of percent  Modes of Regulation of Cholesterol Synthesis 1. Covalent modification of HMG-CoA reductase 2. Transcriptional regulation of HMG-CoA reductase gene 3. Proteolytic degradation of HMG-CoA reductase 1. Covalent modification: Protein phosphorylation AMP-activated protein kinase (AMPK) inactivates HMG-CoA Reductase -ve, +ve +ve  1. HMG-CoA Reductase Is Most Active When Dephosphorylated 1. AMP-dependent protein kinase (AMPK) – when AMP rises, AMPK phosphorylates HMG-CoA-Red. → activity , cholesterol synthesis  2. Glucagon, epinephrine – cascades lead to phosphorylation,  activity HMG-CoA-Red 3. Insulin – cascades lead to dephosphorylation, activity Covalent modification provides short-term regulation. 2. SREBP (Sterol Regulatory Element-Binding Proteins) and Insig (Insulin-induced gene protein) regulate Cholesterol High sterol levels > SREBPs retained in ER with SCAP (SREBP – cleavage activating protein) &, Insig If sterol levels decline, sterol sites on SREBP & Insig empty. SCAP/SREBP complex moves to Golgi and is cleaved. SREBP reg. domain moves to the nucleus. SREBP >Transcription of HMG-CoA reductase and other genes.  3. Regulation of HMG-CoA Reductase by Proteolytic Degradation Insig (insulin-induced gene protein) senses cholesterol levels – binds oxysterol. – triggers ubiquination of HMG-CoA reductase – targets the enzyme for degradation by proteasomes Regulation of Cholesterol Metabolism ACAT = AcylCoA Cholesterol Acyl Transferase  Fatty Acid Metabolism is Tightly Regulated AMPK inactivates ACC. Decrease in malonyl-CoA removes inhibition of FA oxidation  AMP-activated protein kinase (AMPK) Global regulator of energy metabolism AMPK is an energy sensor AMPK responds to wide range of physiological conditions AMPK is a target for treatment of Type II diabetes Metformin inhibits mitochondrial respiratory chain (Complex I) Activates AMPK AMPK is a global regulator of metabolism Inputs to AMPK Targets of AMPK Global regulator of metabolism